Cocaine (COC) abuse and dependence is a major health problem that currently has no FDA approved pharmacotherapies to aid in treatment. Amphetamine (AMPH) has been examined as a potential treatment for COC abuse, with promising behavioral results in rodents, monkeys and humans. It has been proposed that AMPH acts as an agonist replacement therapy, similar to methadone or nicotine patches. However, our data suggest that AMPH may be reducing the reinforcing efficacy of COC by stabilizing the dopamine (DA) system. If AMPH has efficacy as a pharmacotherapy independent of its DA elevating effects, it could lead to the development of more targeted therapeutics with limited abuse potential. Here we aim to determine the neurochemical and behavioral outcomes of AMPH mini-pump treatment during long-access COC self-administration (LgA) and/or during abstinence. We have selected the LgA model as it results in several behavioral and neurochemical changes that parallel those observed in human COC abusers, including escalation of COC intake and tolerance to the DA elevating and behavioral activating effects of the drug. Neurochemical tolerance to COC, along with other DA system alterations such as increased evoked DA release, may underlie escalation of COC intake as well as increased motivation to administer COC, a phenomenon observed following LgA. The specific aims proposed in this application characterize the consequences of COC self-administration and expand on our preliminary data demonstrating that AMPH may reverse LgA-induced neurochemical changes and restore dopaminergic function. In Specific Aim 1 we will determine the ability of AMPH treatment to attenuate COC intake as well as assess alterations to the DA system following LgA and the ability of AMPH mini-pumps to protect against and/or reverse these alterations. In Specific Aim 2 we will examine changes in motivation to administer COC and COC seeking following LgA and the ability of AMPH to prevent/reverse any LgA-induced changes. Although previous literature has demonstrated promising behavioral results suggesting AMPH as a potentially effective treatment for COC abuse, there has been, to our knowledge, no investigation of the neurochemical mechanisms for these results. Our proposed aims explore a comprehensive assessment of the neurochemical and behavioral effects of AMPH administration during COC self-administration, making these studies critical to understanding potential treatment of COC abuse with AMPH and its mechanisms of action.